A. Background Related to Nanoparticulate Compositions
Nanoparticulate active agent compositions, first described in U.S. Pat. No. 5,145,684 (“the '684 patent”), are particles consisting of a poorly soluble active agent having adsorbed onto or associated with the surface thereof a non-crosslinked surface stabilizer. The '684 patent also describes methods of making such nanoparticulate active agent compositions. Nanoparticulate compositions are desirable because with a decrease in particle size, and a consequent increase in surface area, a composition is rapidly dissolved and absorbed following administration.
Methods of making nanoparticulate active agent compositions are described, for example, in U.S. Pat. Nos. 5,518,187 and 5,862,999, both for “Method of Grinding Pharmaceutical Substances;” U.S. Pat. No. 5,718,388, for “Continuous Method of Grinding Pharmaceutical Substances;” and U.S. Pat. No. 5,510,118 for “Process of Preparing Therapeutic Compositions Containing Nanoparticles.”
Nanoparticulate active agent compositions are also described, for example, in U.S. Pat. No. 5,298,262 for “Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization;” U.S. Pat. No. 5,302,401 for “Method to Reduce Particle Size Growth During Lyophilization;” U.S. Pat. No. 5,318,767 for “X-Ray Contrast Compositions Useful in Medical Imaging;” U.S. Pat. No. 5,326,552 for “Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;” U.S. Pat. No. 5,328,404 for “Method of X-Ray Imaging Using Iodinated Aromatic Propanedioates;” U.S. Pat. No. 5,336,507 for “Use of Charged Phospholipids to Reduce Nanoparticle Aggregation;” U.S. Pat. No. 5,340,564 for “Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability;” U.S. Pat. No. 5,346,702 for “Use of Non-Ionic Cloud Point Modifiers to Minimize Nanoparticulate Aggregation During Sterilization;” U.S. Pat. No. 5,349,957 for “Preparation and Magnetic Properties of Very Small Magnetic-Dextran Particles;” U.S. Pat. No. 5,352,459 for “Use of Purified Surface Modifiers to Prevent Particle Aggregation During Sterilization;” U.S. Pat. Nos. 5,399,363 and 5,494,683, both for “Surface Modified Anticancer Nanoparticles;” U.S. Pat. No. 5,401,492 for “Water Insoluble Non-Magnetic Manganese Particles as Magnetic Resonance Enhancement Agents;” U.S. Pat. No. 5,429,824 for “Use of Tyloxapol as a Nanoparticulate Stabilizer;” U.S. Pat. No. 5,447,710 for “Method for Making Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;” U.S. Pat. No. 5,451,393 for “X-Ray Contrast Compositions Useful in Medical Imaging;” U.S. Pat. No. 5,466,440 for “Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with Pharmaceutically Acceptable Clays;” U.S. Pat. No. 5,470,583 for “Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation;” U.S. Pat. No. 5,472,683 for “Nanoparticulate Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,500,204 for “Nanoparticulate Diagnostic Dimers as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,518,738 for “Nanoparticulate NSAID Formulations;” U.S. Pat. No. 5,521,218 for “Nanoparticulate lododipamide Derivatives for Use as X-Ray Contrast Agents;” U.S. Pat. No. 5,525,328 for “Nanoparticulate Diagnostic Diatrizoxy Ester X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,543,133 for “Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles;” U.S. Pat. No. 5,552,160 for “Surface Modified NSAID Nanoparticles;” U.S. Pat. No. 5,560,931 for “Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;” U.S. Pat. No. 5,565,188 for “Polyalkylene Block Copolymers as Surface Modifiers for Nanoparticles;” U.S. Pat. No. 5,569,448 for “Sulfated Non-ionic Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle Compositions;” U.S. Pat. No. 5,571,536 for “Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;” U.S. Pat. No. 5,573,749 for “Nanoparticulate Diagnostic Mixed Carboxylic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,573,750 for “Diagnostic Imaging X-Ray Contrast Agents;” U.S. Pat. No. 5,573,783 for “Redispersible Nanoparticulate Film Matrices With Protective Overcoats;” U.S. Pat. No. 5,580,579 for “Site-specific Adhesion Within the GI Tract Using Nanoparticles Stabilized by High Molecular Weight, Linear Poly(ethylene Oxide) Polymers;” U.S. Pat. No. 5,585,108 for “Formulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays;” U.S. Pat. No. 5,587,143 for “Butylene Oxide-Ethylene Oxide Block Copolymers Surfactants as Stabilizer Coatings for Nanoparticulate Compositions;” U.S. Pat. No. 5,591,456 for “Milled Naproxen with Hydroxypropyl Cellulose as Dispersion Stabilizer;” U.S. Pat. No. 5,593,657 for “Novel Barium Salt Formulations Stabilized by Non-ionic and Anionic Stabilizers;” U.S. Pat. No. 5,622,938 for “Sugar Based Surfactant for Nanocrystals;” U.S. Pat. No. 5,628,981 for “Improved Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal Therapeutic Agents;” U.S. Pat. No. 5,643,552 for “Nanoparticulate Diagnostic Mixed Carbonic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,718,388 for “Continuous Method of Grinding Pharmaceutical Substances;” U.S. Pat. No. 5,718,919 for “Nanoparticles Containing the R(−)Enantiomer of Ibuprofen;” U.S. Pat. No. 5,747,001 for “Aerosols Containing Beclomethasone Nanoparticle Dispersions;” U.S. Pat. No. 5,834,025 for “Reduction of Intravenously Administered Nanoparticulate Formulation Induced Adverse Physiological Reactions;” U.S. Pat. No. 6,045,829 “Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;” U.S. Pat. No. 6,068,858 for “Methods of Making Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;” U.S. Pat. No. 6,153,225 for “Injectable Formulations of Nanoparticulate Naproxen;” U.S. Pat. No. 6,165,506 for “New Solid Dose Form of Nanoparticulate Naproxen;” U.S. Pat. No. 6,221,400 for “Methods of Treating Mammals Using Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors;” U.S. Pat. No. 6,264,922 for “Nebulized Aerosols Containing Nanoparticle Dispersions;” U.S. Pat. No. 6,267,989 for “Methods for Preventing Crystal Growth and Particle Aggregation in Nanoparticle Compositions;” U.S. Pat. No. 6,270,806 for “Use of PEG-Derivatized Lipids as Surface Stabilizers for Nanoparticulate Compositions;” U.S. Pat. No. 6,316,029 for “Rapidly Disintegrating Solid Oral Dosage Form,” U.S. Pat. No. 6,375,986 for “Solid Dose Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate;” U.S. Pat. No. 6,428,814 for “Bioadhesive Nanoparticulate Compositions Having Cationic Surface Stabilizers;” U.S. Pat. No. 6,431,478 for “Small Scale Mill;” U.S. Pat. No. 6,432,381 for “Methods for Targeting Drug Delivery to the Upper and/or Lower Gastrointestinal Tract;” U.S. Pat. No. 6,582,285 for “Apparatus for Sanitary Wet Milling;” and U.S. Pat. No. 6,592,903 for “Nanoparticulate Dispersions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate;” all of which are specifically incorporated by reference. In addition, U.S. Patent Application No. 20020012675 A1, published on Jan. 31, 2002, for “Controlled Release Nanoparticulate Compositions,” and International Application No. WO 02/098565, published on Dec. 12, 2002, describe nanoparticulate active agent compositions, and are specifically incorporated by reference.
Amorphous small particle compositions are described, for example, in U.S. Pat. No. 4,783,484 for “Particulate Composition and Use Thereof as Antimicrobial Agent;” U.S. Pat. No. 4,826,689 for “Method for Making Uniformly Sized Particles from Water-Insoluble Organic Compounds;” U.S. Pat. No. 4,997,454 for “Method for Making Uniformly-Sized Particles From Insoluble Compounds;” U.S. Pat. No. 5,741,522 for “Ultrasmall, Non-aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods;” and U.S. Pat. No. 5,776,496, for “Ultrasmall Porous Particles for Enhancing Ultrasound Back Scatter.” None of these references, or any other reference that describes nanoparticulate compositions, relates to a rapidly dissolving solid or semi-solid gelatin dosage form comprising a nanoparticulate active agent.
B. Background Related to Dosage Formulations
Drug products are currently designed for three groups of individuals: infants, pediatrics, and adults. The needs of infants are different from those of children 2 to 12 years of age, and the needs of children are different from those of adults. Moreover, the needs of the elderly population are different than those of other adults. Another category of individuals needing an alternative drug delivery form are patients with chronic dosage regimens. Repeated dosing of tablets or pills may become problematic for patients having a need for daily dosage regimens. Thus, an alternative dosage form is needed for a variety of patient populations.
Pediatric patients have difficulty swallowing until they reach the age of about 10-16 years old. Younger pediatric patients generally take either chewable tablets, crush and mix regular tablets with food/juice, or take a liquid dosage form. Chewable tablets, generally a good dosage form, do not always sufficiently mask the taste of the active agent. Crushing and mixing regular tablets with food or juice is time-consuming, messy, and not always practical. The difficulty of liquid dosage forms, e.g., syrups, is that they are bulky, do not always taste good, and can be unstable as compared to a solid dosage form, such as a tablet. A practical and new dosage form would be of value for these patients.
With advancements in medical science and the focus on healthy lifestyles, there is projected growth of the elderly population in the U.S. and abroad. Currently, the U.S. population of persons 65 years of age or older receives nearly 30% of the medications prescribed. Moreover, it is anticipated that there may be a rise in the demand for drugs by the elderly. In spite of the disproportionately large demand for prescription pharmaceuticals among the elderly, relatively little attention has been directed to meeting the unique pharmacotherapeutic needs of this age group.
Many older patients experience difficulty in swallowing tablets or capsules and yet the vast majority of dosage forms administered to the elderly are tablets or capsules. Uncoated tablets are convenient and economical to manufacture but are often difficult to swallow and frequently cause discomfort by “hanging” in the throat. Coated tablets and capsules are somewhat easier to swallow but with increasing age and the large number of drug products that are administered to a single individual, this is a source of apprehension. Liquid dosage forms are relatively easy to administer but are more costly, easily spilled, often do not taste good, occupy large volumes of space per dosage unit, and possess stability problems.
As is evident, the needs of the elderly differ from those of other populations and deserve special attention in new drug development, product formulation, product packaging, product labeling, patient information, and product marketing and sales. A practical and new dosage form would be of value for these patients as well as others.
C. Background Related to Gelatin Dosage Forms
A gelatin drug delivery system would be beneficial in achieving ease of administration in both young, older, and chronic dosage patients. However, such a dosage system must exhibit sufficient stability and bioavailability. Without sufficient bioavailability and active agent stability, ease of administration is just a single step in the process of pharmaceutical therapy. Prior art gelatin dosage forms have been unable to solve this dual necessity of bioavailability in combination with active agent stability.
The most typical gelatin drug delivery formulations comprise gelatin coated tablet formulations and gelatin encapsulated solid cores or liquid cores of pharmaceutical agents. One such example is found in U.S. Pat. No. 6,197,787 to Franson et al., which discloses a concentrated drug solution for a soft gelatin capsule filling consisting essentially of: (a) a poorly soluble organic acid drug, such an analgesic, anti-inflammatory agent, anthelmintic, etc.; (b) propylene glycol; (c) sodium hydroxide; and (d) water. However, this dosage formulation is a gelatin capsule and not a solid or semi-solid gelatin formulation.
Another example of a soft gelatin capsule is found in U.S. Pat. No. 6,217,902 to Tanner et al. Tanner et al. disclose a soft gelatin capsule comprising a suspension of a solid phase in a liquid phase, with the solid phase consisting of encapsulated beads having a mean diameter of from about 149 μm to 2500 μm. The beads comprise a coating effective to prevent interaction of the active agent with the liquid phase or the soft gelatin capsule. Tanner et al. fail to disclose a solid or semi-solid gelatin formulation.
An example of a gelatin dosage form has been disclosed by Wunderlich in U.S. Pat. No. 5,932,245 (“the '245 patent”). This patent is directed to a dosage formulation that provides: (a) an inner phase comprising at least one nanoparticle compound having an average size ranging from 10 to 800 nanometers; and (b) an outer phase comprising gelatin, collagen hydrolyzates, or mixtures thereof. The inner phase of this composition is negatively charged and the outer phase is positively charged when the dosage formulation is dissolved in an aqueous solution having a pH of less than 9.5, or the inner phase is positively charged and the outer phase is negatively charged when the dosage formulation is dissolved in an aqueous solution having a pH of higher than 3.5.
This reference differs from the present invention in several aspects. First, the '245 patent requires solubilization of the active agent as part of the process of making the described nanosol compositions. The solubilization is achieved either through the use of a solvent (col. 17, lines 30-34), followed by evaporation of the solvent, or through modification of the pH of the gelatin. For example, an active agent is dissolved in ethanol, isopropanol, methanol, or acetone (col. 18, lines 32-36; col. 20, lines 18-20 and 44-48; col. 22, lines 4-5 and 29; col. 23, lines 30-32) or the active agent is dissolved in the gelatin via modifying the pH of the gelatin (col. 18, lines 52-55; col. 21, lines 23-28 and 43-50; col. 22, lines 61-67). Such solubilization of an active agent is undesirable, as solubilization affects the various properties of the active agent, such as the solidification state of the active agent (i.e., whether the active agent is in an amorphous or crystalline form), stability of the active agent in the aqueous state, how much of the active agent has returned to the solid state, etc. Such solubilization is required because in the compositions of the '245 patent, the gelatin functions to stabilize the nanoparticles of the active agent, as pictured in FIG. 5.
The only way to have the gelatin composition “surround and stabilize” the active agent in the composition of the '245 patent is to first solubilize the active agent in the gelatin, or in a solvent followed by mixing the solvent/active agent solution with the gelatin solution and subsequent evaporation of the solvent.
This is in contrast to traditional nanoparticulate drugs, which do not require solubilization of the active agent. Rather, such compositions utilize a surface stabilizer, such as a surfactant, to stabilize the nanoparticulate size of the active agent following particle size reduction via, for example, milling or homogenization. See e.g., U.S. Pat. No. 5,145,684 for “Surface Modified Nanoparticulate Drugs.” However, the '245 patent teaches that the use of surfactants is undesirable in the disclosed compositions because such surfactants can have side effects and possible toxicity. See col. 4, lines 12-14.
Finally, another drawback to the formulation of the '245 patent is that it does not retain excess water, which is essential for effective redispersability, and hence this dosage form may exhibit poor pharmaceutical bioavailability. This is likely because the gelatin formulation of the '245 patent is not a hydrated gelatin.
Similarly, U.S. Pat. No. 6,066,332 (“the '332 patent”) to Wunderlich et al. describes a gelatin dosage form containing ibuprofen, having a particle size of from 10 to 800 nanometers, in the form of a nanosol. As with the compositions of the '245 patent, the '332 patent requires solubilization of ibuprofen to make the described gelatin formulations. See e.g., col. 8, line 60, through col. 9, line 5; col. 9, lines 15-16 and 31-34. The ibuprofen is dissolved in a solvent such as ethanol, isopropanol, methanol, or acetone (col. 8, lines 60-62; col. 9, lines 31-34; col. 16, lines 13-15), or the ibuprofen is dissolved in the gelatin via modifying the pH of the gelatin (col. 9, lines 10-16; col. 15, lines 28-35). Such solubilization of an active agent such as ibuprofen is undesirable, as described above.
Moreover, as with the '245 patent, another drawback to the formulation of the '332 patent is that it does not retain excess water, which is essential for effective redispersability, and hence this dosage form may exhibit poor pharmaceutical bioavailability.
Another example of a gelatin dosage form is disclosed by Allen et al. in U.S. Pat. No. 6,066,337. This patent is directed to a rapidly dissolving pharmaceutical dosage form produced by combining a particulate support matrix with a pharmaceutical ingredient to form a dosage mixture, followed by forming the dosage mixture into a dosage form. When introduced into an aqueous environment, the dosage form is substantially completely disintegrable within less than about 20 seconds. The particulate support matrix is formed by providing an aqueous composition comprising: (a) an aqueous medium, (b) a support agent comprising a non-hydrolyzed gelatin component having a predetermined net charge, (c) a hydrolyzed gelatin component having a predetermined net charge of the same sign as the non-hydrolyzed gelatin component, (d) a bulking agent, and (e) a volatilizing agent. The hydrolyzed gelatin component has a solubility in aqueous solution greater than that of the non-hydrolyzed component. The aqueous composition is introduced as droplets into a drying chamber heated to a temperature sufficient to cause evaporation of substantially all of the aqueous medium and volatilizing agent from the droplets leaving the support agent in a dried particulate form comprising the particulate support matrix. This formulation fails to retain excess water, which is essential for effective redispersability, and hence the Allen et al. formulation exhibits poor pharmaceutical bioavailability.
None of the described prior art teaches a rapidly disintegrating gelatin-based solid or semi-solid dosage form in which an active and stable ingredient is in a nanoparticulate form, which does not require solubilization of the active agent as part of the process of making the dosage form, and wherein the gel-forming substance retains excess water, thereby providing sufficient pharmaceutical bioavailability. This is significant because the prior art gelatin drug delivery systems fail to retain water in the gel matrix, which therefore inhibits or prevents redispersability, and hence the prior art gelatin formulations exhibit poor pharmaceutical bioavailability. Moreover, prior art gelatin dosage forms required solubilization of component active agents, which is undesirable as solubilization of an active agent can change the active agent's pharmacological and pharmacokinetic characteristics.
There is a need in the art for drug dosage forms having ease of administration, active agent stability, and increased pharmaceutical bioavailability for active agents. The present invention satisfies these needs.